There is growing evidence that infection with hepatitis C virus (HCV) is associated with cognitive dysfunction, which is unrelated to the degree of liver injury. Distinct neurocognitive effects of HCV coinfection were also documented in HIV patients. HCV was thought to be strictly hepatotropic, but there is mounting evidence that it can also replicate in peripheral blood mononuclear cells, including monocytes/macrophages, particularly in HIV-infected patients. We have recently found HCV RNA sequences, including viral replicative forms, in autopsy brain tissue from infected patients, which suggests the possibility of direct local effects of HCV infection. We postulate that extrahepatic replication of HCV is directly related to neurocognitive dysfunction as leukocytes could carry the virus across the blood-brain barrier and infect cells within the central nervous system. The most likely target cells are brain macrophages and microglia. The current proposal is aimed at characterizing HCV neuroinvasion with respect to involved cells and possible effects on gene expression patterns. Specifically, we will: 1. Determine the type of cells infected by HCV in autopsy brain tissue from HIV/HCV coinfected patients using laser capture microscopy (LCM) and immunostaining. 2. Characterize by microarray the gene expression pattern in autopsy brain tissue and in isolated brain macrophage/microglia and neuron cells from HCV-infected patients as compared to uninfected control patients. The proposed study will allow to clarify the biological basis of neurcognitive dysfunction encountered in HCV infected, and particularly in HCV/HIV coinfected patients.